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Tau Cx3cr1

José Joaquín Merino, Vilma Muñetón-Gómez, María-Isabel Alvárez, Adolfo Toledano-Díaz
Microglia and astrocytes are the major source of cytokines in Alzheimer,s disease (AD). CX3CR1 is a delta chemokine receptor found in microglia and its neuronal ligand, Fractalkine, has two isoforms: an anchored-membrane isoform, and a soluble isoform. The reduced soluble fractalkine levels found in the brain (cortex/hippocampus) of aged rats, may be a consequence of neuronal loss. This soluble fractalkine maintains microglia in an appropiate state by interacting with CX3CR1. The ablation of the CX3CR1 gene in mice overexpressing human amyloid precursor protein (APP/PS-1) increased cytokine levels, enhanced Tau pathology and worsened behavioural performance in these mice...
2016: Current Alzheimer Research
Nicole Maphis, Guixiang Xu, Olga N Kokiko-Cochran, Astrid E Cardona, Richard M Ransohoff, Bruce T Lamb, Kiran Bhaskar
Neuroinflammation is one of the neuropathological hallmarks of Alzheimer's disease (AD) and related tauopathies. Activated microglia spatially coexist with microtubule-associated protein tau (Mapt or tau)-burdened neurons in the brains of human AD and non-AD tauopathies. Numerous studies have suggested that neuroinflammation precedes tau pathology and that induction or blockage of neuroinflammation via lipopolysaccharide (LPS) or anti-inflammatory compounds (such as FK506) accelerate or block tau pathology, respectively in several animal models of tauopathy...
2015: Frontiers in Neuroscience
Nicole Maphis, Guixiang Xu, Olga N Kokiko-Cochran, Shanya Jiang, Astrid Cardona, Richard M Ransohoff, Bruce T Lamb, Kiran Bhaskar
Pathological aggregation of tau is a hallmark of Alzheimer's disease and related tauopathies. We have previously shown that the deficiency of the microglial fractalkine receptor (CX3CR1) led to the acceleration of tau pathology and memory impairment in an hTau mouse model of tauopathy. Here, we show that microglia drive tau pathology in a cell-autonomous manner. First, tau hyperphosphorylation and aggregation occur as early as 2 months of age in hTauCx3cr1(-/-) mice. Second, CD45(+) microglial activation correlates with the spatial memory deficit and spread of tau pathology in the anatomically connected regions of the hippocampus...
June 2015: Brain: a Journal of Neurology
Sungho Lee, Guixiang Xu, Taylor R Jay, Sabina Bhatta, Ki-Wook Kim, Steffen Jung, Gary E Landreth, Richard M Ransohoff, Bruce T Lamb
Several Alzheimer's disease (AD) risk genes are specifically expressed by microglia within the CNS. However, the mechanisms by which microglia regulate the pathological hallmarks of AD--extracellular deposition of β-amyloid (Aβ) and intraneuronal hyperphosphorylation of microtubule-associated protein tau (MAPT)--remain to be established. Notably, deficiency for the microglial CX3CR1 receptor has opposing effects on Aβ and MAPT pathologies. CX3CL1, the neuronally derived cognate ligand for CX3CR1, signals both in membrane-anchored and soluble forms...
September 10, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Isabelle St-Amour, Isabelle Paré, Cyntia Tremblay, Katherine Coulombe, Renée Bazin, Frédéric Calon
BACKGROUND: Intravenous immunoglobulin (IVIg) is currently in clinical study for Alzheimer's disease (AD). However, preclinical investigations are required to better understand AD-relevant outcomes of IVIg treatment and develop replacement therapies in case of unsustainable supply. METHODS: We investigated the effects of IVIg in the 3xTg-AD mouse model, which reproduces both Aβ and tau pathologies. Mice were injected twice weekly with 1.5 g/kg IVIg for 1 or 3 months...
2014: Journal of Neuroinflammation
Tomasz Jaworski, Benoit Lechat, David Demedts, Lies Gielis, Herman Devijver, Peter Borghgraef, Hans Duimel, Fons Verheyen, Sebastian Kügler, Fred Van Leuven
Adeno-associated virus (AAV)-mediated expression of wild-type or mutant P301L protein tau produces massive degeneration of pyramidal neurons without protein tau aggregation. We probed this novel model for genetic and structural factors and early parameters of pyramidal neurodegeneration. In yellow fluorescent protein-expressing transgenic mice, intracerebral injection of AAV-tauP301L revealed early damage to apical dendrites of CA1 pyramidal neurons, whereas their somata remained normal. Ultrastructurally, more and enlarged autophagic vacuoles were contained in degenerating dendrites and manifested as dark, discontinuous, vacuolated processes surrounded by activated astrocytes...
October 2011: American Journal of Pathology
Seo-Hyun Cho, Binggui Sun, Yungui Zhou, Tiina M Kauppinen, Brian Halabisky, Paul Wes, Richard M Ransohoff, Li Gan
Aberrant microglial activation has been proposed to contribute to the cognitive decline in Alzheimer disease (AD), but the underlying molecular mechanisms remain enigmatic. Fractalkine signaling, a pathway mediating the communication between microglia and neurons, is deficient in AD brains and down-regulated by amyloid-β. Although fractalkine receptor (CX3CR1) on microglia was found to regulate plaque load, no functional effects have been reported. Our study demonstrates that CX3CR1 deficiency worsens the AD-related neuronal and behavioral deficits...
September 16, 2011: Journal of Biological Chemistry
Kiran Bhaskar, Megan Konerth, Olga N Kokiko-Cochran, Astrid Cardona, Richard M Ransohoff, Bruce T Lamb
Aggregates of the hyperphosphorylated microtubule-associated protein tau (MAPT) are an invariant neuropathological feature of tauopathies. Here, we show that microglial neuroinflammation promotes MAPT phosphorylation and aggregation. First, lipopolysaccharide-induced microglial activation promotes hyperphosphorylation of endogenous mouse MAPT in nontransgenic mice that is further enhanced in mice lacking the microglial-specific fractalkine receptor (CX3CR1) and is dependent upon functional toll-like receptor 4 and interleukin-1 (IL-1) receptors...
October 6, 2010: Neuron
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